Polyiodinated compounds, process of preparation and contrast agent containing them

ABSTRACT

The present invention relates to new polyiodinated compounds of general formula: ##STR1## in which R 1  and R 2 , which are identical to or different from each other, represent a group of formula: ##STR2## and R 3  and R 4 , which are identical to or different from each other, represent a group of formula ##STR3## with R 1 , R 2 , R 3  and R 4  comprising in total at least ten hydroxyls, which can be used in contrast media for radiography. 
     The invention also relates to a process for the preparation of these compounds as well as to a contrast medium containing them.

The present invention relates to new polyiodinated compounds which canbe used in contrast agents for radiography.

The invention also relates to a process for the preparation of thesecompounds and to the contrast agents containing them.

The subject matter of the invention is thus polyiodinated compounds offormula: ##STR4## in which R₁ and R₂, which are identical to ordifferent from each other, represent a group of formula: ##STR5## and R₃and R₄, which are identical to or different from each other, represent agroup of formula ##STR6## in which R₅ and R₆, and R₇ and R₈, which areidentical to or different from each other, represent a hydrogen atom, alinear or branched C₁ -C₆ alkyl, a linear or branched C₁ -C₆ hydroxy- orpolyhydroxyalkyl, optionally additionally containing one or more C₁ -C₆alkoxys, especially methoxy or ethoxy, a linear or branched (C₁ -C₆)alkoxy(C₁ -C₆)alkyl or a linear or branched (C₁ -C₆) hydroxy- orpolyhydroxyalkoxy (C₁ -C₆) alkyl, said substituents R₁, R₂ , R₃ and R₄comprising in total at least ten hydroxyls.

The preferred compounds are those of general formula (I) in which:

R₅, R₆ and R₈ are chosen from --CH₃, --CH₂ OH, --CH₂ --CH₂ OH, ##STR7##R₇ being as defined above. ##STR8## are those in which: R₅ representsthe ##STR9## and R₆ is selected from --CH₃, --CH₂ --CH₂ OH and ##STR10##

Preferred groups ##STR11## are those in which: R₇ is a defined above,##STR12## --CHOH--CH₂ OH and R₈ is selected from ##STR13##

The preferred compounds of the present invention are those in which:

R₁ and R₂ represent ##STR14## and R₃ and R₄ represent

    --NH--CO--CHOH--CH.sub.2 OH                                (compound No. 1);

R₁ and R₂ represent ##STR15## and R₃ and R₄ represent ##STR16## R₁ andR₂ represent ##STR17## and R₃ and R₄ represent

    --NH--CO--CH.sub.3                                         (compound No. 3);

R₁ and R₂ represent ##STR18## and R₃ and R₄ represent ##STR19## R₁ andR₂ represent ##STR20## and R₃ and R₄ represent ##STR21## R₁ and R₂represent ##STR22## and R₃ and R₄ represent ##STR23## R₁ and R₂represent ##STR24## and R₃ and R₄ represent ##STR25## R₁ and R₂represent ##STR26## and R₃ and R₄ represent

    --NH--CO--CH.sub.2 OH                                      (compound No. 8);

R₁ and R₂ represent ##STR27## and R₃ and R₄ represent

    --NH--CO--CHOH--CH.sub.2 OH                                (compound No. 9);

R₁ and R₂ represent ##STR28## and R₃ and R₄ represent

    --NH--CO--CH.sub.2 OH                                      (compound No. 10);

R₁ and R₂ represent ##STR29## and R₃ and R₄ represent

    --NH--CO--CH.sub.3                                         (compound No. 11)

R₁ and R₂ represent ##STR30## and R₃ and R₄ represent

    --NH--CO--CHOH--CH.sub.3                                   (compound No. 12).

The compounds of formula (I) of the present invention can be prepared byalkylation and/or acylation reactions.

The compounds of formula (I) of the present invention can especially beprepared by a process comprising the following stages:

a) coupling benzene derivatives of formulae (II) and (III): ##STR31## Xbeing selected from chlorine, bromine and iodine and R'₁ and R'₂represent --CO₂ R with R representing C₁ -C₆ alkyl, and R'₃ and R'₄represent --NO₂, so as to produce a compound of formula (IV): ##STR32##in which R'₁, R'₂, R'₃ and R'₄ are as defined above; b) amidation of--CO₂ R with an amine ##STR33## R₅ and R₆ being as defined above; c)reduction of nitro groups to amino groups;

d) iodination under conventional conditions;

e) optional protection of hydroxyls using conventional protectivegroups;

f) acylation of aromatic amino groups with an acid chloride of formulaR'₈ --COCl, R'₈ representing a group R₈ as defined above in whichhydroxyls are protected using a conventional protective group; and,either

g) optional alkylation of amido groups with a reagent of formula Z--R₇,Z being a labile group such as Cl, Br or I and R₇ being as definedabove, and deprotection of protected hydroxyls; or

h) deprotection of protected hydroxyls and optionally alkylation ofamido groups with a reagent of formula Z--R₇, Z being a labile groupsuch as Cl, Br or I and R₇ being as defined above.

The reaction of stage a) preferably takes place in a suitable solventsuch as xylene, nitrobenzene, nitrotoluene, DMF or pyridine, in thepresence of a metal catalyst such as copper according to the Ullmanmethod (E. Fanta, Chem. Rev., 64, 613, 1964).

The reaction of stage c) is a catalytic reduction by hydrogen onpalladium charcoal or on Ranney nickel or a chemical reduction.

The iodination reaction of stage d) takes place under usual conditions,such as with aqueous ICl or I₂, in the presence of KI/ethylalnine attemperatures between 0° C. and 100° C.

The acylation and alkylation reactions of stages f) and g) are carriedout under usual conditions, in the presence of a strong base.

The compounds of formula (I) of the present invention can also beprepared by a process comprising the following stages:

a₁) coupling of benzene derivatives of formulae (II) and (III) asdescribed above, so as to obtain the compound of formula (IV) asdescribed above;

b₁) saponification of ester groups --CO₂ R so as to obtain --CO₂ H;

c₁) chlorination under usual conditions of acid groups so as to obtain--COCl;

d₁) amidation of --COCl with an amine of formula ##STR34## R₅ and R₆being as defined above; e₁) reduction of nitro to amino groups;

f¹) iodination under usual conditions;

g¹) optionally protection of --OH using conventional protective groups;

h₁) acylation of aromatic amino groups with an acid chloride of formulaR'₈ --COCl as described above in Stage f), and either;

i₁) optionally alkylation of amino groups with a reagent of formulaZ--R₇ as described above in stage g), and deprotection of --OH, or

j₁) deprotection of --OH and optionally alkylation of amido groups witha reagent of formula Z--R₇ as described above in stage h).

The compounds of formula (I) of the present invention can also beprepared by a process comprising the following stages:

a₂) coupling of benzene derivatives of formulae (II) and (III) ##STR35##X being selected from chlorine, bromine and iodine and R'₁ and R'₂representing --CO₂ R with R representing H or C₁ -C₆ alkyl and R'₃ andR'₄ representing --NO₂, so as to obtain a compound of formula (IV):##STR36## in which R'₁, R'₂, R'₃ and R'₄ are as defined above; b₂)reduction of nitro to amino groups;

c₂) iodination under usual conditions, and either

d₂) chlorination of ⁻ CO₂ R to COCl, followed by

e₂) acylation of aromatic amino groups with an acid chloride of formulaR'₈ COCl, R'₈ representing a R₈ group as defined above, or

d'₂) acylation of aromatic amino groups with an acid chloride of formulaR'₈ COCl, R'₈ representing a R₈ group as defined above, hydroxyls havingbeen protected beforehand, followed by

e'₂) chlorination of --CO₂ R to --COCl, and

f2) amidation of --COCl with an amine of formula ##STR37## R₅ and R₆being as defined above.

The amines of formula ##STR38## used for the reactions of stages f₂) andd₁) mentioned above are, for the most part, known and commerciallyavailable. Additionally, amino alcohols used to produce the preferredcompounds of the present invention, mentioned above, can be prepared inthe following ways:

Preparation of the amino alcohol No. 1 ##STR39## a) Preparation of thecompound of formula ##STR40##

2 g (13.7 mmol) of 2,4-ethylidene-D-erythrose, obtained according to theprocess described in J. Am. Chem. Soc., 2301, 1960, Barker R. et al.,are dissolved in 10 cm³ of water at 30° C. 10 cm³ of an aqueousmethylamine solution (40%) are added dropwise at 0° C. After returningto room temperature, stirring is continued for 2 h. The solution is thenreduced at room temperature in the presence of palladium-on-charcoal.The catalyst is then filtered and the filtrate concentrated to dryness.After solidification in ethyl ether, 1.7 g of the title product areobtained, i.e. a yield of 77%. TLC (dioxane/H₂ O/NH₃ :8/3/2) R_(f) :0.74 TLC (CH₂ Cl₂ /MeOH 8/2) R_(f) : 0.17

¹³ C NMR (DMSO) (δ, ppm) 200 MHz 98.2 (C--CH₃), 80.3 (CH--O), 70.5 (CH₂--O), 63.4 (CHOH), 53.1 (CH₂ --N), 36.5 (NH--CH₃), 20.7 (C--CH₃).

b) Preparation of the compound of formula: ##STR41##

1.5 g (9.3 mmol) of the product obtained in a) are dissolved in 20 cm³of 2N HCl. The solution is stirred at 50° C. for 5 h. Afterconcentration, and purification by passing through H⁺ resin, thesolution is evaporated to dryness. The residue is taken up in ethylether. After filtering and drying, 0.8 g of the title product isobtained (Yield: 64%). TLC (dioxane/H₂ O/NH₃ :8/3/2) R_(f) : 0.18

¹³ C NMR (DMSO) (δ, ppm) 200 MHz 74.5 (CH--CH₂ OH), 69.6 (CHOHCH₂), 63.3(CH₂ OH), 54.7 (CH₂), 36.12 (NHCH₃) MS (DCI/NH₃) m/z; 153 (M+N⁺ H₄); 136(M+H⁺) base peak

Preparation of amino alcohol No. 2 ##STR42## a) Preparation of thecompound of formula: ##STR43##

The compound is prepared according to the method described above.

Reductive amination of 2,4 -ethylidene-D-erythrose (6 g, 41 mmol) iscarried out in the presence of aminopropanediol (1.2 equiv.) in ethanol(40 cm³).

After chromatography on a silica column, the title product is obtainedwith a yield of 73%. TLC (dioxane/H₂ O/NH₃ :8/3/2) R_(f) : 0.73

¹³ C NMR (DMSO) (δ, ppm) (200 MHz) (98, C--CH₃), (80.2-80.5, CH--O),(70.2-70.4, CH₂ --O), (70.3, CHOH), (64.5-64.6, CH₂ --OH), (62.2-63.1,CHOH), (52.9-53, CH₂), (50.8-51, CH₂), (20.5, CH₃).

b) Preparation of the compound of formula: ##STR44##

6 g (29.8 mmol) of the product obtained in the preceding stage aredeprotected by treatment with 5N HCl (50 cm³). The reaction mixture isstirred for 4 h at 50° C. After evaporation, the residue obtained ispurified through H⁺ resin. After concentration and solidification inethyl ether, 2.6 g of the title product are obtained (Yield 54.7%) TLC(dioxane/H₂ O/NH₃ :8/3/2) R_(f) : 0.39

¹³ C NMR (DMSO) (δ, ppm) 74.3 (CH--CH₂ OH, butanetriol chain), 70.3(CH--CH₂)×2, 64.5-64.6 (CH₂ OH, butanetriol chain), 63.3 (CH₂ OH), 52.8(CH₂ N)×2 MS (DCI/NH₃) m/z 196 (M+H⁺) base peak, 178 (M+H⁺ --H₂ O), 160(M+H⁺ --2H₂ O) 136, 122, 109, 92.

Preparation of amino alcohol No. 3 ##STR45##

As with methylamine (for the preparation of amino alcohol No. 1) andaminopropanediol (for the preparation of amino alcohol No. 2),ethanolamine, under the same reductive amination conditions, leads, inthe presence of 2,4-ethylidene-D-erythrose, to the title product.

a) Characteristics of the compound of formula ##STR46## TLC (CH₂ Cl₂/MeOH/NH₃ : 8/2/1) R_(f) : 0.56

¹³ C NMR (DMSO) (δ, ppm) 97.9 (C--CH₃), 80.5 (CH--O), 70.2 (CH₂ OH),62.9 (CHOH), 60.2 (CH₂ --O), 51.6 (CH₂ --N), 50.7 (CH₂ --N), 20.4 (CH₃).

b) Characteristics of the compound of formula ##STR47## TLC (CH₂ Cl₂/MeOH/NH₂ 55/30/10) R_(f) : 0.25 TLC (dioxane/H₂ O/NH₃ : 8/3/2) R_(f) :0.48 ¹³ C NMR (DMSO) (δ, ppm) 74.5 (CHOHCH₂ OH), 70.2 (CHOH--CH₂), 63.5(CHOHCH₂ OH), 60.4 (CH₂ --CH₂ OH), 52.5 (CH₂ --CHOH), 51.8 (CH₂ CH₂ OH).

By taking the operating conditions described above and by using serinolwith 2,4-ethylidene-D-erythrose, the amino alcohol of formula: ##STR48##is prepared in the same way. Preparation of the amino alcohol offormula: ##STR49##

Butene-3,4-diol is prepared from butene-1,4-diol (commercially availablefrom the company Aldrich-Strasbourg) according to the rearrangementmethod described in U.S. Pat. No. 4,661,646.

The epoxidation of butene-3,4-diol is carried out according to themethod described in U.S. Pat. No. 3,352,898 and leads to3,4-epoxy-1,2-butanediol.

The opening of the diol epoxide by benzylamine (0.5 eq.) leads tobis(2,3,4-trihydroxybutyl)benzylamine.

After debenzylation under hydrogen in the presence of palladiumcharcoal, bis(2,3,4trihydroxybutyl)amine is obtained.

It is obvious that the invention encompasses not only the compounds offormula (I) as a racemic mixture but also the stereoisomers such asenantiomers, diastereoisomers, atropoisomers, and syn-anti, endo-exo andE-Z isomers, due to the presence of asymmetric carbon atoms and/or torotational restrictions due to steric hindrance introduced by the iodineatoms and/or by the substituents R₁ to R₄ of the compounds of formula(I).

Another subject matter of the present invention is contrast agents whichcomprise at least one compound of formula (I).

These contrast agents are useful in man and animals for radiologicalpurposes.

The preferred pharmaceutical form of the contrast agents according tothe invention consists of aqueous solutions of the compounds. Accordingto one embodiment of the invention, the compounds are encapsulatedinside liposomes.

The aqueous solutions generally contain a total of 5 to 100 g ofcompounds per 100 ml and the injectable amount of such solutions cangenerally vary from 1 to 1000 ml. The solutions can also containadditives such as a sodium salt, especially sodium citrate, heparin andedetate calcium disodium.

These compositions can be administered by any conventional route usedfor iodinated non-ionic contrast agents. Thus, they can be administeredenterally or parenterally (intravenous routes, intra-arterial,opacification of the cavities) and in particular in the subarachnoidspace.

Examples of the preparation of compounds according to the invention willbe given below.

EXAMPLE 1

Preparation of3,3'-bis[(2,3-dihydroxy)propionyl]amino-5,5'-bis[N-2-hydroxyethyl-N-2,3,4-trihydroxybutyl]carbamoyl-2,2',4,4',6,6'-hexaiodobiphenyl(compound No. 1).

1) Preparation of 3-iodo-5-nitrobenzoic acid

120 g (0.72 mol) of 3-nitrobenzoic acid are added to 122 g (0.53 mol) ofH₅ IO₆ and 400 g (1.57 mol) of iodine dissolved at 10° C. with stirringfor 30 minutes in 2750 ml of 20% oleum. After stirring for 12 hours atroom temperature, this solution is slowly poured into ice. Theprecipitate formed is filtered and then washed with a 20% sodiumbisulphite solution before being dissolved in a sodium hydroxidesolution and then filtered on paper. After acidification with HCl, thereare obtained 170 g of white crystals which are filtered and dried.

Yield=81%

M.p.=172° C. TLC (toluene 60/methyl ethyl ketone 25/HCOOH 5) R_(f) =0.75Iodine purity=99%

¹ H NMR (DMSO) 8.5 ppm (s, 2H aromatic protons) 8.7 ppm (s, 1H aromaticproton) 13 ppm (m, COOH, 1H exchangeable with D₂ O)

2) Preparation of the methyl ester of 3-iodo-5-nitrobenzoic acid

180 g (0.614 mol) of the compound obtained in 1), dissolved in 1800 mlof methanol and 10 ml of 98% H₂ SO₄, are maintained under reflux for 24hours. After evaporation of the methanol to two-thirds, the solutionobtained is cooled and the ester which precipitates is filtered. Afterdissolving the product in 2000 ml of ether, the ethereal phase is washedwith 1000 ml of H₂ O, then dried over MgSO₄ and evaporated to dryness.181 g of white crystals are obtained.

Yield=90%

M.p.=88° C. Iodine purity 99% TLC (CH₂ Cl₂ 70/MeOH 30): R_(f) =0.95 IR1720 (COOCH₃) 1520 (NO₂)

¹ H NMR (DMSO) 3.9 ppm (s, COOCH₃ 3H) 8.5 ppm (s, 2H aromatic protons)8.7 ppm (s, 1H aromatic proton).

3) Preparation of 5,5'-dimethoxycarbony-3,3'-dinitrobiphenyl

86 g (0.28 mol) of the compound obtained in Stage 2) are brought to 220°C. After addition of 86 g of copper, the temperature is progressivelyincreased to 270° C. and 20 g of copper are again added. The mixture ismaintained at this temperature for 1 hour before being cooled. Afterextraction with CH₂ Cl₂ and filtration through Celite, the organic phaseis evaporated to dryness.

The residual paste is washed with 2×500 ml of petroleum ether and thentaken up in ether. The brown precipitate formed is filtered off and thenpurified by silica chromatography. After evaporation, 20 g of browncrystals are obtained.

Yield=40%

M.p.=159° C. TLC (CH₂ Cl₂): R_(f) =0.6

¹ H NMR (DMSO) 3.9 ppm (s, COOCH₃ 6H) 8.5 ppm (2s, 4H aromatic protons)8.7 ppm (1s, 2H aromatic protons)

4) Preparation of 5,5'-dicarboxy-3,3'-dinitrobipheny

14 g (0.038 mol) of the compound obtained in 3) are maintained underreflux for 18 h in 100 ml of a 25% aqueous NaOH solution.

The solution obtained is cooled; after acidification, the precipitateformed is extracted with ethyl acetate and washed with H₂ O. Afterevaporation and washing with ether, 12 g of white crystals are obtained.

Yield=95%

M.p.>300° C. TLC (toluene 60/methyl ethyl ketone 25/HCOOH 25): R_(f)=0.8

¹ H NMR (DMSO): 5.3 ppm (m, COOH, 2H exchangeable with D₂ O) 8.65 to 8.8ppm (3s, 6H aromatic protons).

5) Preparation of 3,3'-dinitro-5,5'-bis(N-hydroxyethyl-N-2,3,4-trihydroxybutyl)carbamoylbiphenyl

1.66 g (0.005 mol) of the compound obtained in 4) are added to asolution of 60 ml of SOCl₂ and 0.1 ml of dimethylformamide. The solutionis maintained under reflux for 5 hours. After distillation of SOCl₂, thepaste obtained is dissolved in CH₂ Cl₂ and poured dropwise at 5° C. intoa solution containing 3.3 g (0.02 mol) ofN-2-hydroxyethyl-N-2,3,4-trihydroxybutylamine and 2.8 ml (0.02 mol) oftriethylamine dissolved in 20 ml of dimethylacetamide. After addition,the mixture is stirred for 1 h at 60° C. and then at room temperaturefor 12 h. After filtration of the triethylamine hydrochloride, thesolvent is evaporated. The paste obtained is purified by passing throughH⁺ /OH⁻ resin and then by chromatography on silica. After evaporation ofthe solvents and passing through H⁺ resin, 3.1 g of white crystals areobtained.

Yield=100% TLC (CH₂ Cl₂ 60/meOH 40) R_(f) : 0.5.

6) Preparation of 3,3'-diamino-5,5'-bis[N-2-hydroxyethyl-N-(2,3,4-trihydroxybutyl)carbamoyl]-2,2',4,4',6,6'-hexaiodobiphenyl

a) Reduction of the nitro groups:

1.3 g (0.002 tool) of the compound obtained in 5) dissolved in 60 ml ofmethanol in a 500 ml autoclave in the presence of 1 g of 10% aqueousPd/C are stirred for 5H at 60° C. under a hydrogen pressure of 6×10⁵ Pa.After filtration of the catalyst, the solution is used in the followingstage. TLC (CH₂ Cl₂ 40/MeOH 60): R_(f) =0.15.

b) Iodination with ICl 4.35 ml (0.024 mol) of a 70% ICl solution areadded dropwise to the solution obtained in Stage a). On completion ofaddition, the reaction mixture is maintained at 80° C. for 18 h and thenleft for 12 h at room temperature. The brown solution obtained isevaporated, then iodination is repeated with 1.45 ml of 70% ICl in 20 mlof MeOH. After 10 h at 80° C., the solvent is evaporated and the pastewashed with acetone. The product is taken up in ether and then dried.2.1 g of white crystals are obtained.

Yield=80% TLC (CH₂ Cl₂ 70/MeOH 30): R_(f) =0.3.

7) Preparation of3,3'-diamino-5,5'-bis[N-acetoxyethyl-N-(2,3,4-triacetoxybutyl)cabomoyl]-2,2',4,4',6,6'-hexaiodobiphenyl

64.6 ml of acetic anhydride are added dropwise at 5° C. to 42 g (0.0317mol) of the compound obtained in 6) dissolved in 300 ml of pyridine.After stirring for 4 h at room temperature, the crude reaction productis poured into ice-cold water acidified with 750 ml of 5N HCl. Theprecipitate formed is filtered off and then taken up in CH₂ Cl₂. Theorganic phase is washed with water and then dried over MgSO₄. Afterevaporation and purification on SiO₂ /eluent ACOEt, there are obtained20 g of white crystals which are washed with ether and dried.

Yield: 38% Iodine purity: 99% TLC (ACOEt) : R_(f) =0.8.

8) Preparation of3,3'-bis[(2-isopropyl-1,3-dioxolan-5-yl)carbonylaminol]-5,5'-bis-[(N-acetoxyethyl-N-(2,3,4,-triacetoxybutyl)carbamoyl]-2,2',4,4',6,6'-hexaiodobiphenyl

a) Preparation of the chloride of4-(2-dimethyl-1-dioxolan-1-3-yl)carboxylic acid.

1.15 ml (0.02 mol) of oxalyl chloride are added to 2.2 g (0.012 mol) ofthe potassium salt of 4-(2-dimethyldioxolan-1-3-yl)carboxylic acid in0.05 ml of pyridine and 12 ml of ether. After stirring for 2 h at 0° C.and then for 18 h at room temperature, the solution is evaporated todryness.

b) The compound obtained in a) is slowly added to a solution of 2.7 g(0.002 mol) of the compound obtained in 7). After 16 h at 35°, thesolution is poured onto Et₂ O. After filtration, white crystals areobtained (3 g).

Yield: 93% TLC (ACOEt) : R_(f) =0.75.

9) Preparation of3,3'-bis[(2-3-dihydroxy)propionyl]-amino-5,5'-bis[N-2-hydroxyethyl-N-(2,3,4-trihydroxybutyl)]carbamoyl-2,2',4,4',6,6'-hexaiodobiphenyl

23 g (0.012 mol) of the compound obtained in 8) are stirred for 18 h atroom temperature in the presence of 3.4 g of K₂ CO₃ in 300 ml of MeOH.After evaporation, the residue is stirred in 150 ml of 2N HCl for 12 hat 25°. After removal of inorganics on H⁺ resin, then OH⁻ resin and thenevaporation, 14 g (78%) of crude product are obtained. Afterpurification on silica, 8 g (60%) of pure compound are obtained. TLC CH₂Cl₂ 50/MeOH 50: R_(f) =0.1% Iodine purity: 99%.

EXAMPLE 2

Preparation of3,3'-bis(acetylamino)-5,5'-bis-[(N-2,3,4-trihydroxybutyl-N,2,3-dihydroxypropyl]carbamoyl-2,2',4,4',6,6'-hexaiodobiphenyl(compound No. 3)

1) Preparation of 5,5'-dicarboxy-3,3'-diaminobiphenyl

28.6 g (0.086 mol) of the compound obtained in 4) of Example 1 aresuspended in 350 cm³ of H₂ O at pH 6.4. 3 g of Pd/C are added and thewhole mixture is hydrogenated under a pressure of 5×10⁵ pascals at 80°C. for 4 hours. The solution obtained after filtration of the Pd/Cthrough Celite is brought back to pH 6 and the amino acid precipitates.

After filtration, 17 g of a cream-colored solid are obtained.

Yield: 78% TLC CH₂ Cl₂ /MeOH/NH₃ :55/30/10 R_(f) =0.8.

2) Preparation of5,5'-dicarboxy-3,3'-diamino-2,2',-4,4',6,6'-hexaiodobiphenyl

14.5 g (0.053 mol) of the compound obtained in 1) are suspended in 10eq. of 70% ICl, 150 cm³ of H₂ O, 600 cm³ of methanol and 2.5 cm³ ofconcentrated HCl. The whole mixture is maintained at 80° C. for 72hours. The reaction mixture is concentrated as much as possible. Thebrown oil obtained is stirred in 750 cm³ of H₂ O for 24 hours. The brownprecipitate obtained is filtered. Crude weight: 46.5 g

Yield: 68% TLC (ethanol): R_(f) =0.7.

3) Preparation of 3,3'-bis(diacetylamino)-5,5'-dicarboxy-2,2',4,4',6,6'-hexaiodobiphenyl

8.8 g (0.086 mol) of the compound obtained in 2) are dissolved in 150cm³ of DMAC and 6.1 cm³ of acetyl chloride (10 eq) and are maintained at45° C. with stirring for 56 hours.

The slightly concentrated reaction mixture is poured onto 200 cm³ ofice-cold H₂ O. After filtration of the precipitate, 10 g of acream-colored solid are obtained.

Yield: 97% TLC (ethanol): R_(f) =0.45.

4) Preparation of 3,3'-bis(diacetylamino)-5,5'-di-(chloroformyl)-2,2',4,4',6,6'-hexaiodobiphenyl

9.3 g (0.0078 mol) of the compound obtained in 3) are dissolved in 100cm³ of thionyl chloride and maintained at reflux for 16 hours. Afterevaporation of the thionyl chloride, the product is crystallized bystirring in pentane. Weight obt.: 9.3 g

Yield: 97% TLC (ethanol): R_(f) =0.8

5) Preparation of 3,3'-bis (acetylamino)-5,5'-bis([(N-2,3,4-trihydroxybutyl-N,2,3-dihydroxypropyl)]carbamoyl-2,2',4,4',6,6'-hexaiodobiphenyl

8.7 g (0.0071 mol) of the compound obtained in 4) are dissolved in 100cm³ of DMAC.

4 cm³ (4 eq.) of triethylamine are added, as well as 5.5 g (4 eq.) ofN-2,3-dihydroxypropyl-N-2,3,4-trihydroxybutylamine.

The whole mixture is maintained at 70° C. for 4 hours (monitored byHPLC). After concentration of the reaction medium, the crude product istaken up in 100 cm³ of H₂ O and brought to pH 10.5 by addition of 2NNaOH and maintained at 50° C. for 5 hours. After removal of inorganicswith H⁺ /OH⁻ resin, and then purification by silica chromatography, 3.5g of the pure compound are obtained. TLC: CH₂ Cl₂ 50/MeOH 50: R_(f)=0.1% Iodine purity: 98%.

EXAMPLE 3

Preparation of3,3'-bis[(2-hydroxymethyl-3-hydroxy)propionyl]amino-5,5'-bis[N-(2-hydroxyethyl)-N-(2,3,4-trihydroxybutyl)carbamoyl-2,2',4,4',6,6'-hexaiodobiphenyl(compound No. 2)

1) Preparation of3,3'-bis[(2-isopropyl-1,3-dioxan-5-yl)-carbonyl]amino-5,5'-bis[N-(2-acetoxyethyl)-N-(2,3,4-triacetoxybutyl)carbamoyl-2,2',4,4',6,6'-hexaiodobipenyl

a) Preparation of the chloride of 2-isopropyl-1,3-dioxanyl-5-carboxylicacid

70 g (0.385 mol) of 2-isopropyl-1,3-dioxanyl-5-carboxylic acid are addedportionwise to a solution of 400 ml of DMAC. The mixture is brought to0° C. and then 31.2 ml (0.423 mol) of SOCl₂ are run in dropwise. Oncompletion of addition, the mixture is left for 5 hours at roomtemperature.

b) 80 g (0.0482 mol) of the compound of Example 1 are added portionwiseto the solution obtained in a). After 24 hours at 45° C., the solutionis precipitated with water. After filtration, the precipitate obtainedis taken up in CH₂ Cl₂. The organic phase is washed with H₂ O and thendried over MgSO₄. After evaporation and purification on SiO₂ (eluentAcOEt), 70 g of beige crystals are obtained.

Yield=73% TLC (AcOEt): R_(f) =0.85.

2) Preparation of3,3'-bis[(2-hydroxymethyl-3-hydroxy)-propionyl]amino-5,5'-bis[N-(2-hydroxyethyl)-N-(2,3,4-trihydroxybutyl)carbamoyl-2,2',4,4',6,6'-hexaiodobiphenyl

70 g (0.0355 mol) of the compound obtained in 1) are stirred for 18hours at room temperature in the presence of 9 g of K₂ CO₃ in 900 ml ofMeOH. After evaporation the residue is stirred in 400 ml of HCl for 12hours at 25° C.

After removing the inorganics with H⁺ resin, then OH⁻ resin and thenevaporation, 41 g (76%) of white crystals are obtained. TLC (CH₂ Cl₂50/MeOH 50): R_(f) =0.2 Iodine purity: 97.5%.

EXAMPLE 4

Preparation of3,3'-bis[2-hydroxypropionylamino]-5,5'-bis[N-(2,3-dihydroxypropyl)-N-(2,3,4-trihydroxybutyl)carbamoyl]-2,2',4,4',6,6'-hexaiodobiphenyl(compound No. 5)

1) Preparation of3,3'-dinitro-5,5-bis(N-2,3-dihydroxypropyl-N-2,3,4-trihydroxybutyl)carbamoylbiphenyl

12.5 g (0.0376 mol) of the compound obtained in 4) of Example 1 areadded to a solution of 100 ml of SOCl₂ and 0.1 ml of DMF. The solutionis maintained at reflux for 5 hours. After distillation of the SOCl₂,the paste obtained is dissolved in CH₂ Cl₂ and poured dropwise at 20° C.into a solution containing 20.5 g (0.105 mol) ofN-2,3-propanediol-N,2,3,4-trihydroxybutylamine and 14.6 ml (0.105 mol)of triethylamine dissolved in 80 ml of DMAC. After addition, the mixtureis stirred for 4 hours at room temperature. After filtration of thetriethylamine hydrochloride, the solvent is evaporated. The pasteobtained is purified by passing on H⁺ resin. After evaporation of thesolvent, 33 g of brown oil are obtained.

Yield=100% TLC (CH₂ Cl₂ /60: MeOH/40): R_(f) =0.15.

Preparation of3,3'-diamino-5,5'-bis[N-2,3-dihydroxypropyl-N-(2,3,4-trihydroxybutyl)carbamoyl]-2,2',4,4',6,6'-hexaiodobiphenyl

a) Reduction of the nitro groups:

21 g (0.0306 mol) of the compound obtained in 1) dissolved in 800 ml ofMeOH in a 1000 ml autoclave in the presence of 12 g of 10% aqueous Pd/Care stirred for 5 hours at 30° C. under a hydrogen pressure of 10⁶ Pa.After filtering the catalyst, the solution is used in the followingstage. TLC (CH₂ Cl₂ /15: MeOH/85): R_(f) =0.15

b) Iodination with ICl:

54 ml (0.3 mol) of a 70% ICl solution are added dropwise to the solutionobtained in Stage a). On completion of addition, the reaction mixture isleft at room temperature for 12 hours. The solution is poured into 2000ml of ether, the precipitate obtained is filtered and then washed withether. After drying, the product obtained is iodinated again with 54 ml(0.3 mol) of 70% ICl in 500 ml of MeOH. After 12 hours at 50° C., thesame treatment as above is applied to the solution. The precipitateobtained is iodinated again for a third time with 27 ml of ICl (0.15mol) in 300 ml of MeOH.

After 12 hours at 50° C., the same treatment as above is applied to thesolution. Cream-colored crystals are obtained. Weight=19 g - Yield=45%TLC (CH₂ Cl₂ /60: MeOH/40): R_(f) =0.25.

3) Preparation of3,3'-diamino-5,5'-bis[(N-2,3-diacetoxypropyl-N-2,3,4-tracetoxybutyl)carbamoyl]-2,2',4,4',6,6'-hexaiodobiphenyl

30 ml of acetic anhydride are added dropwise at 5° to 19 g (0.0137 mol)of the compound obtained in 2) dissolved in 110 ml of pyridine. Afterstirring for 12 hours at room temperature, the crude reaction product ispoured into ice-cold water acidified with 150 ml of 5N HCl. Theprecipitate formed is filtered off and then taken up in CH₂ Cl₂. Theorganic phase is washed with H₂ O and then dried over MgSO₄. Afterevaporation and purification on SiO₂, the eluent AcOEt, 11 g of yellowcrystals are obtained.

Yield=46% Iodine purity=98.2% TLC (ACOEt) : R_(f) =0.8.

4) Preparation of 3,3'-bis[2-acetoxypropionylamino]-5,5'-bis[N-2,3-diacetoxypropyl-N-(2,3,4-triacetoxybutyl)-carbamoyl]-2,2',4,4',6,6'-hexaiodobiphenyl

a) Preparation of the chloride of 2-acetoxypropionic acid

40 ml of thionyl chloride are added dropwise to 50 g (0.378 mol) of2-acetoxypropionylcarboxylic acid dissolved in 60 ml of isopropyl ether.After reflux for 6 hours, the solution is evaporated and the residue isthen distilled under reduced pressure. A white liquid is obtained.

Yield=60% Weight=30 g.

b) Acylation:

5.5 g (0.036 mol) of the compound obtained in a) are added slowly to asolution of 11 g (0.006 mol) of the compound obtained in 3) dissolved in40 ml of DMAC.

After 16 hours at 40° C., the solution is poured into ice-cold water.The product is filtered, taken up in CH₂ Cl₂, washed with H₂ O and thendried over MgSO₄. After evaporation and purification on SiO₂, eluentAcOEt, 3 g of yellow crystals are obtained.

Yield=35% TLC (AcOEt): R_(f) =0.7

5) Preparation of3,3'-bis[2-hydroropionylamino]-5,5'-bis-[N-(2,3-dihydroxpropyl)-N-(2,3,4-trihydroxybutyl)carbamoyl]-2,2',4,4',6,6'-hexaiodophenyl

3 g (0.0015 mol) of the compound obtained in 4) are stirred for 12 hoursat room temperature in the presence of 500 mg of K₂ CO₃ in 60 ml ofMeOH. After evaporation and removal of inorganics through H⁺ resin andthen evaporation, 1 g of product is obtained.

Yield=70% TLC (CH₂ Cl₂ 50/MeOH 50) R_(f) =0.3.

EXAMPLE 5

Preparation of3,3'-bis[(2-hydroxymethyl-3-hydroxypropionyl)amino]-5,5'-bis[N-methyl-N-(2,3,4-trihydroxybutyl)carbamoyl]-2,2',4,4',6,6'-hexaiodobiphenyl-(compoundNo. 6)

1) Preparation of3,3'-dinitro-5,5'-bis(N-methyl-N-2,3,4-trihydroxybutyl)carbamoylbiphenyl

80 g (0.241 mol) of the compound obtained in 4° of Example 1 are addedto a solution of 600 ml of SOCl₂ and 0.1 ml of DMF. The solution ismaintained at reflux for 5 hours. After distillation of the SOCl₂, thepaste obtained is dissolved in CH₂ Cl₂ and poured dropwise at 20° C.into a solution containing 78 g (0.578 mol) ofN-methyl-2,3,4-trihydroxybutylamine and 80 ml (0.578 mol) oftriethylamine dissolved in 500 ml of DMAC. After addition, the mixtureis stirred for 4 hours at room temperature. After filtration of thetriethylamine hydrochloride, the solvent is evaporated. The pasteobtained is purified by passing on H⁺ resin. After evaporation of thesolvent, 150 g of brown oil are obtained.

Yield=100% TLC (CH₂ Cl₂)/75: MeOH/50): R_(f) =0.3

2) Preparation of3,3'-diamino-5,5'-bis[N-methyl-N-(2,3,4-trihydroxybutyl)carbamoyl]-2,2',4,4',6,6'-hexaiodobiphenyl

a) Reduction of the nitro groups.

20 g (0.0353 mol) of the compound obtained in 1) above in 700 ml ofmethanol in a 1000 ml autoclave in the presence of 10 g of 10% aqueousPd/C are stirred for 5 hours at 30° C. under a hydrogen pressure of 10⁶Pa. After filtering the catalyst, the solution is used in the followingstage. TLC (CH₂ Cl₂ /40: MeOH/60): R_(f) =0.4.

b) Iodination with ICl 62 ml (0.353 mol) of a 10% ICl solution are addeddropwise to the solution obtained in Stage a). On completion ofaddition, the reaction mixture is left at room temperature for 12 hours.The solution is poured into 2000 ml of ether, the precipitate obtainedis filtered and then washed with ether. After drying, the productobtained is iodinated again with 31 ml of 70% ICl (0.17 mol) in 300 mlof MeOH. After 12 hours at 50° C., the same treatment as above isapplied to the solution. Cream-colored crystals are obtained.

m=21 g

Yield=55% TLC (CH₂ Cl₂ /70: MeOH/30): R_(f) =0.4.

3) Preparation of3,3'-diamino-5,5'-bis[N-methyl-N-(2,3,4-triacetoxybutyl)carbamoyl]-2,2',4,4',6,6'-hexaiodobihenyl

17.8 ml of acetic anhydride are added dropwise at 5° to 11.4 g (0.009mol) of the compound obtained in 2) dissolved in 68 ml of pyridine.After stirring for 12 hours at room temperature, the crude reactionproduct is poured into ice-cold water acidified with 75 ml of 5N HCl.The precipitate formed is filtered off and then taken up in CH₂ Cl₂. Theorganic phase is washed with H₂ O and then dried over MgSO₄. Afterevaporation and purification through SiO₂, eluent AcOEt, 9 g of whitecrystals are obtained.

Yield=66% Iodine purity=98% TLC (ACOEt) R_(f) =0.8

4) Preparation of 3,3'-bis[(2-isopropyl-1,3-dioxan-5-yl)carbonylamino]-5,5'-bis[N-methyl-N-(2,3,4-triacetoxybutyl)carbamoyl]-2,2',4,4',6,6'-hexaiodobiphenyl

a) Preparation of the chloride of 2-isopropyl-1,3-dioxan-5-ylcarboxylicacid

1.8 g of 2-isopropyl-1,3-dioxan-5-ylcarboxylic acid (10.5×10⁻³ mol) aredissolved in 10 ml of DMAC. The mixture is brought to 0° C. and then0.85 ml (12×10⁻³ mol) of SOCl₂ are added dropwise. After addition, themixture is left for 5 hours at room temperature.

b) Acylation

2 g (1.32×10⁻³ mol) of the compound obtained in 3) are added to thesolution obtained in a). After 12 hours at 45° C., the solution ispoured into H₂ O. After filtration, the product is taken up in CH₂ Cl₂,washed with H₂ O and then dried over MgSO₄. After evaporation andpurification through SiO₂, eluent AcOEt, 1 g of crystals is obtained.

Yield=50% Iodine purity=98.5% TLC (AcOEt) R_(f) =0.85

5) Preparation of3,3'-bis[(2-hydroxymethyl)-3-hydroxypropionylamino]-5,5'-bis[(N-methyl-N-(2,3,4-trihydroxybutyl)carbamoyl]-2,2',4,4',6,6'-hexaiodobiphenyl

6 g (0.00328 mol) of the compound obtained in 4) are stirred for 12hours at room temperature in the presence of 0.6 g of K₂ CO₃ in 70 ml ofmethanol. After evaporation, the residue is stirred in 40 ml of 5N HClfor 12 hours at room temperature. After removal of the inorganicsthrough H⁺ resin and then OH⁻ resin, and then evaporation, 3.75 g ofwhite crystals are obtained.

Yield=78% Iodine purity: 98.7% TLC (CH₂ Cl₂ /50: MeOH/50) R_(f) =0.2

We claim:
 1. Polyiodinated compounds of general formula: ##STR50## inwhich R₁ and R₂, which are identical to or different from each other,represent a group of formula: ##STR51## and R₃ and R₄, which areidentical to or different from each other, represent a group of formula##STR52## which R₅ and R₆, and R₇ and R₈, which are identical to ordifferent from each other, represent a hydrogen atom, a linear orbranched C₁ -C₆ alkyl, a linear or branched C₁ -C₆ hydroxy- orpolyhydroxyalkyl, optionally additionally containing one or more C₁ -C₆alkoxys, a linear or branched (C₁ -C₆) alkoxy(C₁ -C₆)alkyl or a linearor branched (C₁ -C₆) hydroxy-or polyhydroxyalkoxy(C₁ -C₆)alkyl, saidsubstituents R₁, R₂, R₃ and R₄ comprising in total at least tenhydroxyls.
 2. Polyiodinated compounds of formula (I) according to claim1, in which ##STR53## represents ##STR54## or ##STR55##
 3. Polyiodinatedcompounds of formula (I) according to claim 1, in which ##STR56##represents ##STR57## or ##STR58## R₇ being as defined in claim
 1. 4.Polyiodinated compounds of formula (I) according to claim 1, in which R₁and R₂ are identical and represent ##STR59## ##STR60## or R₃ and R₄being identical and as defined in claim
 1. 5. Polyiodinated compounds offormula (I) according to claim 1, in whichR₁ and R₂ represent ##STR61##and R₃ and R₄ represent

    --NH--CO--CHOH--CH.sub.2 OH;

R₁ and R₂ represent ##STR62## and R₃ and R₄ represent ##STR63## R₁ andR₂ represent ##STR64## and R₃ and R₄ represent

    --NH--CO--CH.sub.3 ;

R₁ and R₂ represent ##STR65## and R₃ and R₄ represent ##STR66## R₁ andR₂ represent ##STR67## and R₃ and R₄ represent ##STR68## R₁ and R₂represent ##STR69## and R₃ and R₄ represent ##STR70## R₁ and R₂represent ##STR71## and R₃ and R₄ represent ##STR72## R₁ and R₂represent ##STR73## and R₃ and R₄ represent

    --NH--CO--CH.sub.2 OH;

R₁ and R₂ represent ##STR74## and R₃ and R₄ represent

    --NH--CO--CHOH--CH.sub.2 OH

R₁ and R₂ represent ##STR75## and R₃ and R₄ represent

    --NH--CO--CH.sub.2 OH;

R₁ and R₂ represent ##STR76## and R₃ and R₄ represent

    --NH--CO--CH.sub.3

R₁ and R₂ represent ##STR77## and R₃ and R₄ represent

    --NH--CO--CHOH--CH.sub.3.


6. Process for the preparation of the compounds of formula (I) accordingto claim 1, comprising the steps of:a) coupling compounds of formulae:##STR78## X being selected from chlorine, bromine and iodine and R'₁ andR'₂ representing --CO₂ R,R being C₁ -C₆ alkyl and R'₃ and R'₄representing --NO₂, in a suitable solvent in the presence of a metalcatalyst to produce a compound of formula (IV): ##STR79## b) amidationof --CO₂ R with an amine of formula ##STR80## R₅ and R₆ being as definedin claim 1; c) reduction of nitro groups to amino groups; d) iodinationunder usual conditions; e) optional protection of hydroxyls usingconventional protective groups; f) acylation of aromatic amino groupswith an acid chloride of formula R'₈ --COCl, R'₈ corresponding to R₈ asdefined in claim 1 in which hydroxyls are protected; and, either g)optional alkylation of amido groups with a reagent of formula Z--R₇, Zbeing a labile group selected from Cl, Br and I and R₇ being as definedin claim 1, and deprotection of protected hydroxyls, or h) deprotectionof protected hydroxyls and optionally alkylation of amido groups with areagent of formula Z--R₇, Z being a labile group selected from Cl, Brand I and R₇ being as defined in claim
 1. 7. Process for the preparationof the compounds of formula (I) according to claim 1, comprising thefollowing steps:a) coupling of benzene derivatives of formulae (II) and(III): ##STR81## X being selected from chlorine, bromine and iodine andR'₁ and R'₂ representing --CO₂ R with R representing H or C₁ -C₆ alkyland R'₃ and R'₄ representing --NO₂, so as to obtain a compound offormula (IV): ##STR82## in which R'₁, R'₂, R'₃ and R'₄ are as definedabove, b) reduction of nitro to amino groups, c) iodination under usualconditions, and either d) chlorination of --CO₂ R to COCl, followed bye) acylation of aromatic amino groups with an acid chloride of formulaR'₈ COCl, R'₈ representing a R₈ group as defined in claim 1, or d')acylation of aromatic amino groups with an acid chloride of formula R'₈COCl, R'₈ representing a R₈ group as defined in claim 1, hydroxylshaving been protected beforehand, followed by e') chlorination of --CO₂R to COCl, and f) amidation of COCl with an amine of formula ##STR83##R₅ and R₆ being as defined in claim
 1. 8. Contrast agent for radiologyby X-rays, comprising at least one compound according to claim
 1. 9.Contrast agent according to claim 8, consisting of an aqueous solutionof the compound(s).